A-to-I editing of miR-579-3p exacerbates neonatal hypoxic-ischemic brain injury via regulation of ABCD3-dependent lipid metabolism in astrocytes.

BACKGROUND

Neonatal hypoxic-ischemic brain injury (HIBD) often results in high morbidity and mortality, with a complicated pathogenesis. This investigation is focused on uncovering the role and mechanism of edited miR-579-3p in HIBD.

METHODS

Western blot analysis and RT-qPCR were employed to examine the expression of protein and mRNA. To assess cell proliferation and apoptosis, MTT, EdU, and flow cytometry assays were utilized. Commercially available kits were obtained to detect ROS level. The VLCFA concentration was determined through ELISA. A dual-luciferase reporter assay verified the miRNA targets.

RESULTS

Increased editing level of miR-579-3p at position 4 induced by ADAR2 enzyme was observed in HIE patients, which was related to HIE clinical grade. Functionally, wild-type and edited miR-579-3p showed opposite effect on astrocytes activity. Specifically, ed-miR-579-3p restrained the cell viability of astrocytes with OGD/R treatment and accelerates apoptosis. Mechanically, A-to-I RNA editing alters the targets of miR-579-3p. And ed-miR-579-3p obtains novel target ABCD3 and loses TRAF6. TRAF6 overexpression restrained the cell viability of astrocytes with OGD/R treatment, which was not affected by edited miR-579-3p. Further, edited miR-579-3p restrained the cell viability of astrocytes with OGD/R treatment by impairing ABCD3-mediated β-oxidation of VLCFA. In vivo experiment also demonstrated that edited miR-579-3p aggravated brain damage in HIBD by impairing ABCD3-mediated astrocytes lipid metabolism.

CONCLUSION

Edited miR-579-3p aggravates brain damage in HIBD by impairing ABCD3-mediated VLCFA β-oxidation of astrocytes.